Exploring Tumors in Context: Jain’s Work Blazes Trail on Microenvironment

When Rakesh K. Jain, PhD, joined the field of cancer research, most experts believed that knowing everything possible about cancer cells was the sole key to a cure.

Yet Jain was convinced that the abnormal microenvironment around a tumor was also a big part of what fueled a cancer, and needed to be considered when treating the disease.

Few were interested in his opinion.

As a young assistant professor of Chemical and Biomedical Engineering at Columbia University in the mid-1970s, Jain’s first six requests for research grants, all focused on the role of tumor microenvironment in drug delivery and efficacy, were rejected.

When a decade passed and the idea still hadn’t really caught on, Jain decided he needed to teach anyone who would listen, one by one, no matter how long it took. So he launched what he believes was the first course on tumor microenvironment at any university in the United States or abroad, an intensive week-long class that began with an enrollment of just a handful of students but has since moved to Harvard University, along with the doctor, and become extremely popular.

In the meantime, Jain, who is the Andrew Werk Cook Professor of Tumor Biology (Radiation Oncology) at the Harvard Medical School and director of the Edwin L. Steele Laboratory for Tumor Biology at Massachusetts General Hospital (MGH), has helped drive major advances in the understanding of tumor pathophysiology.

His work involves normalizing tumor vessels and microenvironment so that cancer medicines such as chemotherapy, radiation, and immune therapy can be better delivered and more effective. An important way to achieve that, he has found—although it seems counterintuitive— is through the use of antiangiogenic agents, which were designed to starve tumors but, at low doses, actually help normalize their chaotically organized and leaky blood vessels.1,2 The first to discover the antiangiogenic properties of trastuzumab, Jain’s lab also works to identify biomarkers meant to better guide the use of such therapies.

To facilitate that work, Jain and his colleagues have developed an array of imaging technologies, innovative mathematical models, and sophisticated animal preparations— including the implantation of transparent windows into mice to allow direct observation of tumors, the genes within them, and the host stroma around them.

Last year, all of that work came full circle, gaining resounding recognition when Jain received the Science of Oncology Award given by the American Society of Clinical Oncology (ASCO). It was an indication that Jain is now regarded as a pioneer in oncology for integrating the principles of engineering with biology to improve treatment and creating a unique approach to cancer research.

Building that wide acceptance of the importance of tumor environment has sometimes been frustrating, the 62-year-old scientist acknowledges.

“New music or art is not usually accepted right away, so why should it be different for science?” Jain asked. “As much as we’d like to be impatient and say, ‘Why don’t they get it?’ it’s human nature.”

Busy but Joyful Days

It’s inside the Steele Lab, a division of about 80 scientists and support staff, that Jain continues to push his research forward, working most closely with a group of four assistant professors, four associate professors, and a cadre of fellows, graduate students, and technicians from diverse disciplines including engineering, mathematics, physics, chemistry, molecular and cellular biology, genetics, immunology, pathology, radiology, radiation, medical oncology, neuro-oncology, pediatric oncology, and surgical oncology.

At the same time, the doctor is “tightly engaged” as a scientific leader of clinical trials—22 in the last decade, all dedicated to finding biomarkers for the success of, or resistance to, antiangiogenic therapies in the treatment of various malignancies and some nonmalignant tumors, such as schwannoma.

“I’m not an MD, so I don’t conduct trials myself, but we are very much involved in designing these trials and analyzing the resulting data, interpreting it, and helping to use that information to design new preclinical and clinical studies,” Jain said. “In all of these trials, the biomarker work was done in the Steele Lab, which is renowned worldwide for its translational research.”

At this stage of his career, Jain’s colleagues and students are often surprised to find that he spends little time traveling to conferences to lecture or present study results. While Jain previously dedicated a lot of time to such activities, he decided a decade ago to limit his trips out of town to about a dozen a year.

Maurie Markman, MD, offers examples of clinical trials where the interpretation of study results is worthy of considerable additional discussion or where justification for the actual conduct of the study can be called into question.